Synthesis of imidazoles



United States Patent SYNTHESIS OF HVIIDAZOLES William J. Paleveda, Iselin, and Erwin F. Schoenewaldt,

Metuchen, N.J., assignors to Merck 8: Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Application February 28, 1958 Serial No. 718,121

7 Claims. (Cl. 260- 309) This invention relates generally to a process for making imidazoles. More particularly it relates to a new and novel process for preparing di lower alkyl 4,5-imidazoledicarboxylates. Still more specifically, it is concerned with a novel synthesis of a di-lower alkyl 4,5-imidazoledicarboxylate from a di-lower alkyl tartrate dinitrate.

A synthesis of 4,5-imidazoledicarboxylic acid from tartaric acid is known in the art. This reported method, however, suffers serious disadvantages in that it gives the desired imidazole in only very low yields or under difficulty controllable reaction conditions, and is not amenable to large scale operation. It is an object of this invention to provide a new synthesis of di-lower alkyl 4,5- imidazoledicarboxylates from a di-lower alkyl tartrate dinitrate. It is a further object to provide such a synthesis wherein high yields of the imidazole compounds are obtained and the desirable reaction conditions are readily achieved and maintained. It is an additional object of the invention to make available a feasible synthesis of di-lower alkyl 4,5-imidazoledicarboxylates. Our invention is of significant importance in that di-loweralkyl 4,S-imidazoledicarboxylate may be converted by treatment with concentrated aqueous ammonia to 4,5-imidazoledicarboxamide. This latter substance is very active in the prevention of poulary coccidiosis when fed to chickens as a component of the chick feedstufi.

According to this invention, it has been found that di-lower alkyl 4,S-imidazoledicarboxylates are produced in good yield by reacting a di-lower alkyl tartrate dinitrate with either a lower aliphatic aldehyde or formaldehyde or a formaldehyde precursor, and ammonium ion in an acidic reaction medium having a pH in the range of about 3.5 to about 6.5. This process may be illustrated by the follow flow sheet:

wherein R is a lower alkyl radical having from one to six carbon atoms and R is hydrogen or a lower alkyl hyde such as acetaldehyde or proprionaldehyde is used the lower alkyl imidazole dicarboxylate obtained is substituted in the 2-position with a lower alkyl group, and

there are realized in this way compounds such as 2-methy1 diethyl 4,S-imidazoledicarboxylate, 2-propyl dimethyl 4,Sdmidazoledicarhoxylate, 2-methy1 dibutyl 4,5-imidazoledicarboxylate and the like. However, in the preferred embodiment of the invention, we employ formaldehyde or a precursor thereof such as paraformaldehyde or hexamethylenetetramine, as the aldehyde, obtaining thereby imidazoles substituted only at the 4 and 5 positions, such as dimethyl 4,5-imidazoledicarboxylate, diethyl 4,S-imidazoledicarboxylate and dibutyl 4,5-imidazoledicarboxylate. While it has been found most convenient under our optimum reaction conditions to use formaldehyde itself, it should be understood that substances which are known to give rise to formaldehyde under acidic conditions, e.g. hexamethylenetetramine and paraformaldehyde, are equally satisfactory. It is our belief that such substances generate formaldehyde in situ in the reaction mixture, but the exact mechanism of reaction is not definitely known and we do not wish to be bound by this belief. We employ at least one mole of aldehyde per mole of di-loWer alkyl tartrate dinitrate, but prefer for best results to use a significant molar excess of aldehyde, and particularly from a to a molar excess thereof. Larger amounts may, of course, be used with no adverse effects on the success of the process.

Ammonium ion also participates in the conversion of a di-lower alkyl tartrate dinitrate to di-lower alkyl 4,5- imidazoledicarboxylate. We prefer to employ aqueous ammonia as source of ammonium ion, but other sources such as liquid ammonia or an ammonium salt such as the acetate, chloride, bromide, phosphate, citrate and the like, are satisfactory and may be used if desired. In order to obtain optimum yields of di-lower alkyl 4,5-imidazoledicarboxylate by the method of our invention it is desirable toemploy at least 3 moles of ammonium ion per "mole of di-lower alkyl tartrate dinitrate, and preferably from 4 to 8 moles of ammonium ion per mole of tartrate dinitrate. It will, of course, be appreciated that larger amounts of ammonium ion may be utilized without adverse eifect on the reaction. Furthermore, substances which generate ammonium ions or the equivalent thereof in an acidic medium may be employed instead of adding ammonium ion as such to the reaction. Thus, we have found that hexamethylenetetramine, in addition to serving as a source of precursor of formaldehyde as discussed above, may also be successfully employed to furnish ammonium ions to the reaction.

It is an important feature of our process that the pH of the reaction mixture be maintained within certain limits during the actual reaction period. The reaction mixture should be acidic, and have a pH between about 3.5 and about 6.5, and preferably an initial pH of about 4.5 to 6.5. The pH tends to drop as the reaction proceeds but this is not harmful as long as it does not become too acidic. We prefer to adjust and control the pH of the reaction medium by use of a suitable buffer system. The system acetic acid-ammonium acetate is particularly suitable for this purpose as ammonium ion is simultaneously supplied to the reaction, but other buffers such as acetic acid-sodium acetate and acetic acid-potassium acetate, citric acid-citrate and phosphate buffer may also be employed. Alternatively and instead of the buffer system, the desired pH may be maintained by continuous or semi continuous addition of a base, such as ammonium hydroxide or an alkali metal hydroxide during the reaction period.

As the acid component of the reaction mixture, we have found it desirable to employ a weak acid, and preferably acetic acid. However, any acid may be used as long as the pH is held within the limits referred to acetic acid has been found to be very suitable in this respect. It is preferred, however, to use an aqueous organic solvent medium where the organic solvent is a water-miscible polar solvent such as a lower alkanol, ethylene glycol, dioxane, dimethylformamide, acetone and the like. The organic solvent should be one which is inert under reaction conditions and which will act as a solvent for the reactants. Aqueous methanol, aqueous ethanol, aqueous isopropanol and aqueous ethylene glycol are very satisfactory solvent media for our reaction.

The reaction temperature is not overly critical although it should not be less than about C. since at very low temperatures the di-lower alkyl tartrate dinitrate reacts slowly to form the lower alkyl 4,5-imidazoledicarboxylate. Temperatures of 10400" C., and preferably of about 50-90 C. are'satisfactory for the process, and it has been found most convenient to conduct the process at the reflux temperature of the reaction mixture. The reaction time is likewise not critical and it will be appreciated that the optimum time will depend to a large extent on reaction temperature. At the preferred temperatures of about 5090 C., the process is substantially complete in one-half to one and one-half hours.

The di-lower alkyl 4,5-imid-azoledicarboxylates obtained according to our invention, such as dimethyl 4,5- imidazoledicarboxylate, diethyl 4,5-tr'midazoledicarboxylate, dibutyl 4,5-imidazoledicarboxylate, dipropyl 4,5-imidazoledicarboxylate and dihexyl 4,5-imidazoledicarboxylate may be recovered and isolated by dilution of a the reaction mixture with water. The desired product precipitates and is isolated by methods such as filtration or centrifugation. The di-lower alkyl 4,5-imidazoledicanboxylates are readily converted by treatment with 4. resulting precipitate of 4,5-imidazoledicarboxamide is then removed by filtration and dried. It weights 13.4

grams.

Acidification of an aqueous solution of the sodium salt of this latter compound yields substantially pure 4,5- imidazoledicarboxamide.

7 Example 2 0.0162 mole of dibutyltartrate dinitrate is added dropwise at 15 C. to a solution of 17 'ml. of methanol, 17 ml. of water, 4 ml. of glacial acetic acid, 7.1 grams of ammonium acetate and 1.77 grams of hexamethylenetetramine. The resultant mixture is stirred at room temperature for about 15 hours and. then diluted with an equal volume of water, The soliddibutyl 4,5-imidazoledicarboxylate thus'obtained is removed by filtration and dried. The material weights 2.8 grams (64.5% of theoretical). Upon recrystallization from aqueous methanol there is obtained substantially pure ester, melting point 1075-1085." C.

xa pl 3 0.0162 mole of dibutyl tartrate dinitrate is charged dropwise at.1 5 C to a mixture of 17 ml. of methanol, 17 ml. of water, 4 ml. of glacial acetic acid, 7.1 grams of ammonium acetate and 1.77 grams of hexamethylenetetramine. The reaction mixture is stirred at room temperatu fc for 16 hours. To the resulting thick slurry of crystalline dibutyl 4,5-imidazoledicarboxylate in the reac- Example 4 A solution of 4.53 grams of hexamethylenetetramine, 6.9 grams of ammonium chloride, 35 ml. of methanol and 30ml. of water is adjusted to a pH of 6.5 with 2.5 Nfhydrochloric acid. 0.02 91 mole of dibutyl tartrate 1 dinitrate is added to this solution at a temperature of concentrated aqueous ammonia to the corresponding diamides. Thus, compounds such as dimethyl 4,Simidazoledicarboxylate, diethyl 4,5-imidazoledicarboxylate and dibutyl 4,5-imidazoledicarboxylate are converted by treatment with concentrated aqueous ammonia to 4,5- imidazoledicarboxamide, a substance which is very active in preventing poultry coccidiosis. alternatively, the lower alkyl 4,S-imidaboledicarboxylates obtained by the process of this invention may be converted directly, without isolation, to the 4,5-imidazoledicarboxarnide by treatment of the intact reaction mixture with concentrated aqueous ammonia. V

The di-lower alkyl tartrate dinitrates used as starting materials for this invention are prepared from the corresponding di-lower alkyl tartrates by nitration of the latter substance with fuming nitric acid in the presence of concentrated sulfuric acid in the cold for about 15-30 minutes. V

The following examples are given for purposes of illustration and not by way of limitation:

Example 1 To a solution of 90 grams of ammonium acetate and 10 grams of hexarnethylenetetramine in 250 ml of glacial acetic acid there is added dropwise ethyl tartrate di-nitrate prepared from 30 grams of ethyl tartrate. The addition is carried out at 1215 C. over a period of 25 minutes. The reaction mixture is stirred at 15 C. for one hour and then at room temperature for three hours. At the end of this time the solution of diethyl 4,5-imidazoledicarboxylate is concentrated in vacuo to a thicksyrup and added to 500 ml. of concentrated aqueous ammonia at 15 C. The resultant mixture is stirred overnight. The

11-415 .C. 14% aqueo s ammoniu hydroxide is added as required to maintain the pH of the reaction mixture between 6 and 6.5. The reaction is allowed to continue forthree hours, during which timeS ml. of aqueous ammonia is required to maintain the desired pH. Ammonia addition is then stopped and the mixture stirred for about 15 hours at about 15" C. At the end of this time the precipitated dibutyl 4,S-imidazoledicarboxylate is filtered off and dried. It weights 5.055 grams.

Example 5 (A) A solution of 11 ml. of glacial acetic acid, 5 ml. of aqueous concentrated formal in, 9.4 ml, of aqueous concentrated ammonia and 10 mi. of methanol is heated to C. The pH of the mixture is 5.5. To this hot solution is added 0.034 mole of dibutyl tartrate dinitrate over a period'of about 10 minutes. The mixture is then heated at 80 C. for an additionai 15 minutes, and cooled to room temperature, at which time the solution has a pH of about 4.2. It is diluted with an equal volume of cold' water whereby dibutyl 4,S-imidazolediearboxylate is precipitated. This latter product is removed by filtration, washed with water and dried. It weighs 6.46 grams.

Five grams of dibutyl 4,S-imidazolediearboxylate and 5.0 m1. of 28% aqueous ammonia are shaken together in a pressure bottle for 5 /2 hours at 45 C. The precipitated 4,5-irnidazoledicarb0Xamidc s removed by filtration, water-washed and air-dried. It weighs 2.55 grams.

.(B) Dibutyl 4,5-imidazoledicarboxylate is obtained in essentially the same yield as in Example 5A, when the procedure of that example is repeated using 10 ml. of ethylene glysel, ethanol or isopropanol in place of the alities??? Ex Example 6 To a solution of 80 ml. of water and 20.3 ml. of 85% phosphoric acid is added 26.6 ml. (0.394 mole) of concentrated aqueous ammonia and 11.2 grams of hexamethylenetetramine. The pH of the resulting solution is 5.9. Thirty ml. of methanol is then added, the solution warmed to 40 C. and 35.5 grams (0.1008 mole) of butyl tartrate dinitrate added dropwise. The temperature of the reaction mixture is held at 50-60 C. with external cooling. The reaction mixture is then warmed at 60-70 C. for 45 minutes, cooled, and extracted with 100 ml. of chloroform. The chloroform extract is evaporated to dryness in vacuo and the residue of dibutyl 4,S-imidazoledicarboxylate thus obtained is stirred with 20 ml. of methanol and 90 m1. of concentrated aqueous ammonia for 72 hours. 4,5-imidazoledicarboxamide is obtained by filtering the amidation reaction mixture, and water-washing and air-drying the precipitate.

Example 7 To a solution of 9 ml. of glacial acetic acid, 1.0 ml. of water and 3.75 ml. of acetaldehyde is added 9.4 ml. of concentrated aqueous ammonia dropwise at a temperature below 20 C. This mixture is warmed to 30 C. and 10 ml. of di-n-butyl tartrate dinitrate is added dropwise over a 15 minute period. The temperature rises to 82 C. and is maintained there for an additional 15 minutes. The reaction mixture is cooled, diluted with 50 ml. of water and extracted with chloroform. The chloroform solution is dried over magnesium sulfate, and evaporated to dryness in vacuo to yield a crude product which is recrystallized from aqueous methanol to yield di-nbutyI-Z-methyl 4,5-imidazoledicarboxylate.

Analysis.Calcd. for C H N O C, 59.56; H, 7.84; N, 9.84. Found: C, 59.96; H, 7.87; N, 10.07.

Example 8 To a solution of 2.5 ml. of glacial acetic acid, 1.0 ml. of concentrated hydrochloric acid and 2.5 ml. of aqueous formalin is added, with stirring and external cooling, 4.7 ml. of concentrated aqueous ammonia. ml. of methanol is then added. The pH of the solution after methanol addition is 5.7. This mixture is warmed to 60 C. and 5 ml. of dibutyl tartrate dinitrate added dropwise over a five minute period. The reaction mixture is held at the reflux temperature (84 C.) for 15 minutes and then cooled to room temperature. The pH at this point is 3.5. This mixture is diluted with an equal volume of water whereupon dibutyl 4,S-imidazoledicarboxylate precipitates. It is isolated by filtration, washed with water and air-dried. There is obtained 2.94 grams of dibutyl 4,5-imidazoledicarboxylate.

Example 9 to 6 C., 27.2 grams of di-n-butyl tartrate is added 6 dropwise over a 15 minute period. The mixture is aged for 15 minutes, and the organic layer is then separated, washed with cold water and dried under reduced pressure. The di-n-butyl tartrate dinitrate thus obtained weighs about 36 grams.

Other di-lower alkyl tartrate dinitrates are obtained in like fashion from the corresponding di-lower alkyl tartrate.

Example 10 A solution of 9.85 grams (0.0703 mole) of hexamethylenetetramine in 15 ml. water and 10 m1. methanol is heated with 6.2 ml. of glacial acetic acid to bring it to a pH of 5.3. 6.05 grams of butyl tartrate dinitrate is added to the solution at 70-80 C. over a 10 minute period. The mixture is then heated under reflux for an additional 20 minutes. At the end of this time the reaction mixture contains 46% of the theoretical amount of di-n-butyl-4,S-imidazoledicarboxylate.

Any departure from the above description which conforms to the present invention is intended to be included Within the scope of the claims.

What is claimed is:

l. The process which comprises treating a di-lower alkyl tartrate dinitrate with ammonium ion and an aldehyde of the formula R'CHO at a pH of about 3.5 to about 6.5 thereby forming a compound having the formula wherein R is a lower alkyl radical and R is selected from the class consisting of hydrogen and a lower alkyl radical.

2. The process which comprises treating a di-lower alkyl tartrate dinitrate with ammonium ion and a sub stance selected from the class consisting of formaldehyde and compounds which function as sources of formaldehyde at a pH of about 3.5 to about 6.5 thereby forming di-lower alkyl 4,5-imidazoledicarboxylate.

3. The process of claim 2 wherein the reaction is carried out at an elevated temperature.

4. The process of claim 3 wherein the source of formaldehyde is hexamethylenetetramine.

5. The process of preparing dibutyl-4,5-imidazoledicarboxylate which comprises treating dibutyl tartrate dinitrate with formaldehyde and ammonium ion in a reaction medium having a pH of about 3.5 to 6.5.

6. The process of claim 5 wherein the reaction is carried out at an elevated temperature.

7. The process of preparing diethyl-4,5-imidazoledicarboxylate which comprises treating diethyl tartrate dinitrate with formaldehyde and ammonium ion in a reaction medium having a pH of about 3.5 to 6.5.

References Cited in the file of this patent Fargher et al.: J. Chem. Soc., vol. 115, pp. 217-227 (1919).

Snyder et al.: Org. Syntheses, vol. 22, pp. -68

Elderfield: Heterocyclic Compds, vol. 5, p. 212 (1957). 

1. THE PROCESS WHICH COMPRISES TREATING A DI-LOWER ALKYL TARTRATE DINITRATE WITH AMMONIUM ION AND AN ALDEHYDE OF THE FORMULA R''CHO AT A PH OF ABOUT 3.5 TO ABOUT 6.5 THEREBY FORMING A COMPOUND HAVING THE FORMULA 